Various known drugs, including some which are local anesthetics, are synthetic products that can be considered as derivatives of a benzoic acid ester or amide and a tertiary amine having a hydrocarbon chain between these groups.
Thus, these molecule have 3 portions:
a) a lipophilic group, i.e., an arylic or aromatic moiety that includes an ester or amide group; PA1 b) an hydrophilic group, the amine function; and PA1 c) an aliphatic moiety that connects both functions. PA1 1) topical or superficial, useful for mucoses; PA1 2) intradermal or subcutaneous anesthesia; PA1 3) regional anesthesia; PA1 4) epidural anesthesia; and PA1 5) rachidial or spinal anesthesy. PA1 a) depolarizing velocity of phase 0 is reduced; PA1 b) conductibility velocity is reduced; PA1 c) the action potential is slightly narrowed; PA1 d) the automatism decays (phase 4); PA1 e) cardiac excitability is reduced; and PA1 f) the effective refractory period is smaller. PA1 a) in the first step, a distribution of the drug in brain, heart, liver, kidney, skeletal muscle and adipose tissue is observed. PA1 b) the second step consists in the metabolization of the drug in the liver and its excretion in urine.
Local anesthetic drugs are capable of blocking nervous conductibility when administered locally. The simple direct contact of the drug with nerve tissue produces paralysis of the tissue.
There are various common types of local anesthesia including, for example:
Those skilled in the art are normally familiar with this type of anesthesia.
Local anesthetic drugs can act by infiltration in the nerves. For acting by blocking the nervous conductibility, the drug must reach the nerve fibers penetrating the sheets that surround them. In this sense, the drug must be sufficiently hydrosoluble enough to diffuse among tissues and sufficiently liposoluble to penetrate across the lipidic layers of the membranes. In this way, the velocity of action of the drug depends upon its chemical nature, its concentration--a gradient is necessary--and of the type of nerve fiber, since in myelinated axons, the drug can only penetrate by the spaces corresponding to Ranvier nodes. Different diameter fibers offer more or less area to absorb the drug, which also modifies the velocity of action of the drug.
Local anesthetics are usually applied in the form of salts, specially as hydrochlorides. The salts are prepared by the combination of a strong acid with a weak alkali. Since they are acidic, with a pH of 4.0 to 6.0, they are highly soluble in water and highly ionized.
In contact with the alkalinity of the extracellular fluids, the tertiary amines are reformed and, since they are weakly alkaline and are poorly ionized, this part of the molecule can exert its effect.
The increasing of the pH of anesthetic drugs increase proportionally their potency, and it is convenient to increase this pH in those preparations used for topical use, since mucous membranes do not have an adequate buffer system to reform amines in the same manner as extracellular fluid.
The nervous stimulus runs along the nerve fiber by changing the polarity of the membrane, which originates a propagate potential. The local anesthetics, procaine and lidocaine, are capable of interrupting the nervous stimulus and this effect is due to a stabilization of the cell membrane that decreases the permeability of the cell membrane to sodium. Under normal conditions, sodium penetrates from the extracellular to the intracellular fluids to produce such a potential.
As is known, plasma cell membranes are comprised of a lipid bilayer covered by a hydrophilic protein layer, external and internally. Local anesthetics join themselves to the lipid bilayer by means of the lipophilic portion thereof and to the protein layer by means of the hydrophilic properties. In this way, the normal functions of the membrane are altered, disturbing the ionic exchange that normally occur.
These kinds of drugs can cause depression and/or stimulation of the central nervous system which is manifested as anxiety, tremor and convulsions, including those of the epileptoid type. These effects are directly proportional to the potency of the anesthetic.
The stimulation phenomena leads to depressive phenomena, in part due to fatigue of nervous centers and in part to a direct effect of the drug. This can lead to stupor, unconsciousness, areflexia and also death due to a bulbar respiratory center paralysis.
Experiments have demonstrated that procaine and lidocaine exert an anticholinergic effect manifested by blocking the cardioinhibitory effect of vagal stimulation. Lidocaine has been used as an antiarrythmia drug. In animals and human beings, high dosage can produce a reduction in cardiac contractility and hypotension.
Lidocaine, when administered in high dosage, can produce apnea by means of a bulbar respiratory center paralysis and also produces a marked reduction in cough reflex when is administered intravenously. It also has an antagonistic effect for acetylcholine, histamine and barium chlorhydride on bronchial smooth muscle fibers.
Anesthetic drugs, especially lidocaine, have a minor bacteriostatic and bactericidal effect directed to some kind of bacteria, such as Staphylococcus and E. coli.
None of the anesthetic agents are absorbed by intact skin. Instead, in injured skin, with removal of the corneal layer, absorption occurs, either with solutions or creams. In this case, maximal serum levels are achieved 6 to 10 minutes later.
Mucosal absorption differs among mucoses and is very fast in pharynx, tracheobronchial mucosa, lungs (aerosolization), conjunctiva and urethra and is low in bladder mucosa. There exist differences in mucosal absorption among the different drugs. i.e.: lidocaine is faster than other products such as procaine.
Oral route leads to low plasma levels, since the hepatic flow of blood drained from the gastrointestinal tract favors the quick degradation of the drug while parenteral routes lead to a fast absorption rate by a quick passage to blood stream. In accord with this, adrenaline is frequently added to retard the time of absortion and to extend the local effect. When absorbed, these drugs quickly reach the blood stream and are distributed in all tissues. The metabolism is different for each of the drugs of this pharmacological group.
Once procaine is absorbed, or when is administered intravenously, it is hydrolyzed by the enzyme pseudocholines-terase. This enzyme acts directly in blood plasma and in the liver, cleaving the drug to para-aminobenzoic acid and diethyl-aminoethanol. This cleavage is very fast (20 mg. per minute). The resulting products are excreted in urine. The half life of procaine is about 0.7 minutes.
With respect to other esteric local anesthetics, it can be said that pseudocholinesterase also cleaves them, but at a lower rate. i.e.: tetracaine is cleaved at a velocity about 5 times more slowly than procaine.
Since lidocaine is not an ester but rather is an amide, pseudocholinesterase cannot cleave it. Its cleavage is performed in the liver by means of oxidation, hydrolysis, des-ethylation and sulphoconjugation of the metabolites. The resulting metabolites are eliminated in the urine. Half life of lidocaine is about 20 minutes.
The pharmacokinetics of other amide anesthetics are not as well known as lidocaine, but in general terms, it is similar to that of the lidocaine. One of these amide products, prilocaine, when it is metabolized, produces a derivative, ortho-toluidine, which is responsible for the metahemoglobinemia observed when high dosage of prilocaine is administered.
Procaine and lidocaine have a low toxicity, and high dosages are required to produce signs and symptoms of intoxication. Up to 25 g of procaine were administered intravenously in one anesthetic therapy. In spite of this, sometimes, dosages of about 10 to 100 mg are sufficient enough to produce severe complications, attributed to idiosyncrasy of the drug. Toxic manifestations are nervous, cardiovascular or hematological.
Allergic reactions are not common and they consist in cutaneous manifestations, such as urticaria, angioneurotic edema, bronchospasm and, exceptionally, anaphylactic shock.
These drugs have few contraindications, since they do not affect parenchymatic tissues. The contraindications derive from the existence of hypersensitivity to the drug, but, in spite of this, they must be administered with special care in patients with myocardial disease, hepatic dysfunction and severe anemias.
Therapeutic uses of procaine and lidocaine administered by intravenous route include global anesthesia.
In some countries, procaine is used to produce a global anesthesia, administering it by intravenous route. This method is not dangerous: there was only one death in over more than 6200 patients treated with procaine (less than 0.01%).
Lidocaine hydrochloride is used in ventricular arrythmias.
Other uses of procaine include eutrophic and revitalizing effects.
Some years ago, procaine was used as a revitalizing and eutrophic agent. A series of 7,600 patients over 70 years old were treated with procaine, registering a good response, in the sense that they presented a better muscular tone, better hearing, and better intellectual functions. Another series of experiments in a similar group did not find modifications in the parameters measured. Today, it is believed that the use of procaine as a revitalizing and eutrophic agent is not justified.
The effects of lidocaine on cardiovascular system is similar to that of quinidine, and it is believed that its effect is due to its stabilizing property on plasma cell membranes.
Administration of lidocaine produces the following effects on myocardial cells:
It must be said that ventricular fibers are more sensitive to lidocaine than auricular fibers.
Cardiac excitability is depressed by lidocaine (a negative bathmotropic effect), with a high electric stimulation threshold. The fibrillation threshold is also higher, so this drug is an antiarrhythmic agent. The ratio relative refractory period/lasting of action potential is increased.
As a consequence of a decay of depolarizing velocity and of a reduction in the capability of response of the membrane, conductibility is reduced (a negative dromotropic effect).
High dosage of lidocaine can produce reduction of the auriculoventricular conductibility, with a longer lasting of the P-R interval and of the QRS complex.
Lidocaine has little or no effect on normal sinoauricular node, but the drug reduces the automatism of ectopic foci (a negative chronotropic effect).
Contractility is not affected by lidocaine, but high dosage administered intravenously can reduce contractility (a negative inotropic effect).
Lidocaine can effectively suppress ventricular extrasystolia and tachycardia, having minor effects on auricular extrasystolia, tachycardia and fibrillation.
Lidocaine produces, when is administered intravenously, a reduction in arterial tension. Since the drug does not reduce the hypertensive effect of adrenaline, but does reduce that of the nicotine, the hypotensive effect of lidocaine is due to a sympathetic ganglionar blocking.
Administered by oral route, only 35% of the amount of lidocaine is absorbed, and 60% of it is metabolized during the first passage through the liver. Administered by intramuscular route, absorption is efficient and 30 minutes later adequate plasma levels of lidocaine are found, lasting at least for 2 hours.
After intravenous injection, plasma levels of lidocaine decay quickly in two steps:
The therapeutic plasma level of lidocaine is 0.2 to 0.5 mg/100 ml, and the toxic level is 0.7 to 0.9 mg/100 ml.
From blood lidocaine is retained in heart, brain, liver, kidney, skeletal muscle and adipose tissue, but 1 hour later, tissue levels are significantly reduced. This reduction is due to a fast metabolization in the liver. The metabolic derivatives and about 5 to 10% of the intact drug are excreted in urine. The half life of the drug is about 20 minutes.